Project Abstract Because bacterial infection is not only responsible for dental caries but also the main cause of failure of dental restorations, development of dental biomaterials with long-term antibacterial efficacy is an important goal. Although a variety of strategies have been proposed to incorporate antibacterial properties within dental resins, each strategy has intrinsic limitations. Burst release generally occurs when free antibacterial agents are incorporated into resins; surface inhibition of bacterial growth by immobilized quaternary ammonium salt (QAS) can be compromised by surface adsorption of biomolecules; color stability is an issue when inorganic antibacterial fillers are used. Surprisingly, conjugation of antibiotics into the polymer-based resin matrices for the development of antibacterial dental biomaterials has not been explored. The central hypothesis of this proposal is that dental restorative biomaterials based on polymer-antibiotic conjugates (PACs) can offer optimal antibacterial properties, while maintaining their favorable physical and biocompatibility properties. Therefore, this proposal aims to systematically prepare PACs and PAC-containing resins, and study their structure-property relationship in the context of dental restorative applications, with two specific aims. Specific Aim 1 is to develop PACs and PAC-containing dental resins. Monomer-antibiotic conjugates (MACs) will first be prepared. Then PACs will be synthesized by polymerization of MACs with a monomer typically used in dental adhesive applications. The resulting PACs will be used as antibacterial additives in dental adhesives to prepare a library PAC-containing dental resins. MACs, PACs and PAC-containing resins will be systematically characterized to verify the success of the synthesis and to reveal their structural features. Specific Aim 2 is to understand the antibacterial, physical and biocompatibility properties of PACs and PAC-based dental resins. The release profiles of conjugated antibiotics under bio-relevant conditions will be investigated. Their bacterial inhibition effects will be studied systematically by using different oral bacterial species. Their risk of inducing antibiotic resistance will be evaluated. Their biocompatibility with gingival fibroblasts will be assessed. The relationship between their structures, antibacterial properties and biocompatibility will be interpreted. Synergistic effects of multiple antibiotics and combinations of antibiotic(s) with immobilized QAS will be studied. Mechanical properties, water adsorption, contact angle and color stability of the PAC-containing resins will be investigated. Overall, the proposed studies promise to not only establish the synthetic methodology for PACs and PAC-based antibacterial resins, but also provide key insights into their structure-property relationship. These studies will lay a solid foundation for the further development of antibiotic-containing dental formulations for a variety of in vivo clinical applications. The proposed research activities are strongly supported by the interdisciplinary expertise of our research team and the significant preliminary results, which demonstrate not only the feasibility of the synthesis of ciprofloxacin-based PACs and PAC-based resins, but also their remarkable antibacterial benefits.